Recognition of Rab6 by the dynein adaptor BicD2.

Abstract

The dynein adaptor Bicaudal D2 (BicD2) recognizes cargo for dynein-dependent transport and links them to the motor complex. In addition, BicD2 also has a key role in the activation of dynein for processive motility. BicD2-dependent transport pathways are important for brain and muscle development. BicD2 also recruits dynein to Rab6, facilitating the transport of vesicles from and towards the Golgi apparatus. We recently established a structural basis of how BicD2 recognizes Nup358 which facilitates a nuclear positioning pathway that is essential for brain development. Our data suggest that BicD2 recognizes Nup358 by a short cargo recognition α-helix. It is conceivable that the other BicD2 cargoes are recognized by similar α-helical motifs. To test this hypothesis, we identified the BicD2-binding site on Rab6GTP by a combination of mutagenesis and biophysical methods. We found that the binding site of BicD2 is located in a region of Rab6GTP, which undergoes conformational changes in the GTP-bound state compared to the GDP-bound state, explaining why GTP-bound Rab6 has a higher affinity for BicD2. Furthermore, similar as observed for Nup358, the Rab6GTP region that binds to BicD2 is intrinsically disordered, and we propose that it transitions from a random coil conformation to a cargo-recognition alpha-helix in the BicD2/Rab6GTP complex. Our results provide insights into the molecular mechanism of cargo selection of BicD2, which facilitates transport pathways that are important for brain development, transport of Golgi-derived vesicles and faithful chromosome segregation.